Glucocorticoid-induced TNF receptor family-related protein ligand is requisite for optimal functioning of regulatory CD4+ T cells

Gongxian Liao, Michael S. O'Keeffe, Guoxing Wang, Boaz van Driel, Rene de Waal Malefyt, Hans Christian Reinecker, Roland W. Herzog, Cox Terhorst

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Glucocorticoid-induced tumor necrosis factor receptor family-related protein (TNFRSF18, CD357) is constitutively expressed on regulatory T cells (Tregs) and is inducible on effector T cells. In this report, we examine the role of glucocorticoid-induced TNF receptor family-related protein ligand (GITR-L), which is expressed by antigen presenting cells, on the development and expansion of Tregs. We found that GITR-L is dispensable for the development of naturally occurring FoxP3+ Treg cells in the thymus. However, the expansion of Treg in GITR-L-/- mice is impaired after injection of the dendritic cells (DCs) inducing factor Flt3 ligand. Furthermore, DCs from the liver of GITR-L-/- mice were less efficient in inducing proliferation of antigen-specific Treg cells in vitro than the same cells from WT littermates. Upon gene transfer of ovalbumin into hepatocytes of GITR-L-/-FoxP3(GFP) reporter mice using adeno-associated virus (AAV8-OVA) the number of antigen-specific Treg in liver and spleen is reduced. The reduced number of Tregs resulted in an increase in the number of ovalbumin specific CD8+ T effector cells. This is highly significant because proliferation of antigen-specific CD8+ cells itself is dependent on the presence of GITR-L, as shown by in vitro experiments and by adoptive transfers into GITR-L-/-Rag-/- and Rag-/- mice that had received AAV8-OVA. Surprisingly, administering aCD3 significantly reduced the numbers of FoxP3+ Treg cells in the liver and spleen of GITR-L-/- but not WT mice. Because soluble Fc-GITR-L partially rescues aCD3 induced in vitro depletion of the CD103+ subset of FoxP3+CD4+ Treg cells, we conclude that expression of GITR-L by antigen presenting cells is requisite for optimal Treg-mediated regulation of immune responses including those in response during gene transfer.

Original languageEnglish (US)
Article numberArticle 35
JournalFrontiers in immunology
Issue numberFEB
StatePublished - 2014
Externally publishedYes


  • CX3CR1
  • Flt3L
  • GITR-L
  • TNFSF18
  • Treg

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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